Rolipram potentiates bevacizumab-induced cell death in human glioblastoma stem-like cells.

Autor: Ramezani S; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran., Vousooghi N; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran., Kapourchali FR; Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada., Hadjighasem M; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran., Hayat P; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran., Amini N; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran., Joghataei MT; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Neuroscience Department, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address: mt.joghataei@yahoo.com.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2017 Mar 15; Vol. 173, pp. 11-19. Date of Electronic Publication: 2017 Feb 12.
DOI: 10.1016/j.lfs.2017.02.005
Abstrakt: Aims: Glioblastoma cancer stem-like cells (GCSCs) promote themselves proliferation by secreting the vascular endothelial growth factor A (VEGF A ) in an autocrine manner, positively regulated by phosphodiesterase IV (PDE4). In the current study, we investigated the putative cytotoxic effect of bevacizumab, a VEGF A blocker, alone and in combination with a specific inhibitor of PDE4 called rolipram on GCSCs isolated from human surgical tumor specimen with a focus on PI3K/AKT pathway.
Main Methods: CD133+/CD15+ GCSCs were characterized by flow cytometry and expanded in a serum-free primary culture system. The cell survival, apoptosis, and protein expression values were measured using MTT assay, TUNEL staining and western blot, successively. Intracellular cAMP and free secreted VEGF A levels were assessed by cAMP enzyme immunoassay and ELISA, respectively.
Key Findings: Bevacizumab suppressed GCSCs survival with IC 50 ~6.5μg/ml and enhanced the levels of apoptosis, p53 and cleaved-caspase3 along with a decrease in free VEGF A levels and ERKs activation. However, there was no significant modulation of AKT phosphorylation on serine 473, the intracellular PDE4A, VEGF A and cAMP levels. More cytotoxicity in co-treated cells coupled with a more substantial decline in the free VEGF A levels and a greater increase in the quantities of p53 and cleaved-caspase3 compared to those treated with bevacizumab alone. Co-treatment reduced phospho-AKT, endogenous VEGF A and PDE4A values but elevated cAMP levels.
Significance: This study highlighted a booster cytotoxic effect of combined rolipram and bevacizumab treatment on the GCSCs primary culture, suggesting that this approach is warranted in treatment of GBMs overexpressing VEGF A and PDE4A.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: